GLADIATOR: Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction

• Sponsor: Amsterdam UMC, location VUmc (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05672134
• Collaborator: (none)
• Enrollment: 40
• Arms: 2
• Anticipated Duration (Months): 24

Study Details

Study Description

Brief Summary

The goal of this double-blind randomized, placebo-controlled cross-over trial is to evaluate the effectiveness of GerenylGeranylAcetone (GGA) in patients with Heart Failure with a preserved ejection fraction.

The main questions it aims to answer are:

• What is the effect of GGA on diastolic function?

• What is the effect of GGA on endothelial function?

Main study tasks:

• Participants will be treated with either GGA or placebo for 13 weeks. After this they will have a break (wash-out) period for 6 weeks and then cross over to the other study arm.

• Cardiac function will be measured using echocardiogram in all participants

• Renal measurements and endothelial measurements will be performed on the participants.

• Participants will perform a 5 minute walking distance test for functional capacity.

• Participants will fill out questionnaires to score signs & symptoms.

Researchers will compare the patients to themselves to see if the drug improves diastolic- and endothelial function.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Preserved Ejection Fraction	Diagnostic Test: Iohexol measurement; Drug: Geranylgeranylacetone (GGA); Diagnostic Test: Echocardiography; Diagnostic Test: 6-minute walking distance test; Diagnostic Test: EndoPAT; Diagnostic Test: Para-amino Hippuric Acid test; Diagnostic Test: Electrocardiogram	Phase 2

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: crossover multi-centre, double-blind, randomized control trial.crossover multi-centre, double-blind, randomized control trial.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction
• Anticipated Study Start Date: Feb 1, 2023
• Anticipated Primary Completion Date: Feb 1, 2025
• Anticipated Study Completion Date: Feb 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental arm Patients will receive 13 weeks of experimental treatment, followed by a 7 week wash-out period, continuing with 13 weeks of placebo as per crossover design.	Diagnostic Test: Iohexol measurement; Invasive renal hemodynamic measurement of mGFR through the administration of Iohexol.; Drug: Geranylgeranylacetone (GGA); 13 weeks of treatment with GGA/placebo orally, followed by a wash-out period of 6 weeks, then reversal of the treatment arms.; Diagnostic Test: Echocardiography; The investigators will perform echocardiography to find changes in cardiac function.; Diagnostic Test: 6-minute walking distance test; 6 minute walking distance test to compare exercise tolerance in participants.; Diagnostic Test: EndoPAT; Use of EndoPAT to measure endothelial function.; Diagnostic Test: Para-amino Hippuric Acid test; PAH-measurement to measure ERPF.; Diagnostic Test: Electrocardiogram; 12-lead Electrocardiogram
Placebo Comparator: Placebo arm Patients will receive 13 weeks of placebo treatment, followed by a 7 week wash-out period, continuing with 13 weeks of experimental treatment as per crossover design.	Diagnostic Test: Iohexol measurement; Invasive renal hemodynamic measurement of mGFR through the administration of Iohexol.; Drug: Geranylgeranylacetone (GGA); 13 weeks of treatment with GGA/placebo orally, followed by a wash-out period of 6 weeks, then reversal of the treatment arms.; Diagnostic Test: Echocardiography; The investigators will perform echocardiography to find changes in cardiac function.; Diagnostic Test: 6-minute walking distance test; 6 minute walking distance test to compare exercise tolerance in participants.; Diagnostic Test: EndoPAT; Use of EndoPAT to measure endothelial function.; Diagnostic Test: Para-amino Hippuric Acid test; PAH-measurement to measure ERPF.; Diagnostic Test: Electrocardiogram; 12-lead Electrocardiogram

Outcome Measures

Primary Outcome Measures

1. Filling pressures [after 13 weeks of treatment]

   Changes in echocardiography determined filling pressures (E/e')?

2. Endothelial function [after 13 weeks of treatment]

   Changes in EndoPAT®-derived reactive hyperemia index (RHI)

Secondary Outcome Measures

1. Left atrial volumes [After 13 weeks of treatment]

   Changes in echogardiographic measured left atrial volume index (LAVI)

2. Left atrial global strain [After 13 weeks of treatment]

   Changes in echogardiographic measured LA global strain (LAGS)

3. Left atrial emptying fractions [After 13 weeks of treatment.]

   Changes in echogardiographic LA emptying fractions. Formula: (LA maximum volume-LA minimum volume)/LA maximum volume × 100%

4. Left Ventricular global longitudinal strain [Ater 13 weeks of treatment]

   Changes in echocardiographically determinded LV global longitudinal strain (LGS)

5. Left Ventricular Myocardial relaxation [Ater 13 weeks of treatment]

   Change in echocardiographically determined myocardial relaxation (e')

6. Left Ventricular distensibility [After 13 weeks of treatment]

   Change in echocardiographically determined LV distensibility, measured by E.

7. Right Ventricular systolic function [After 13 weeks of treatment]

   Change in echocardiographically determined RV TAPSE

8. Pulmonary Artery Pressure [After 13 weeks of treatment]

   Change in echocardiographically determined PAP

9. Patient reported symptoms [After 13 weeks of treatment]

   Evaluation of symptoms using New York Heart Association class (NYHA)

10. Quality of life assessment [After 13 weeks of treatment.]

    Evaluation of quality of life using the Kansas City Cariomyopathy Questionnaire

11. Functional capacity [After 13 weeks of treatment.]

    Evaluation of Functional Capacity using 6-minute walking distance test (6MWD)

12. CRP (inflammatory biomarker) [After 13 weeks of treatment]

    Changes in CRP concentration in serum

13. Nitrosated hemoglobin (microvascular marker) [After 13 weeks of treatment]

    Changes in Nitrosated hemoglobin (Hb(NO)4) concentration in serum

14. Nitrate (microvascular marker) [After 13 weeks of treatment]

    Changes in nitrate concentration in serum

15. Endothelin-1 (microvascular marker) [After 13 weeks of treatment]

    Changes in Endothelin-1 concentration in serum

16. H2S (microvascular marker) [After 13 weeks of treatment]

    Changes in H2S concentration in serum

17. Measured Glomerular Filtration Rate (mGFR) [After 13 weeks of treatment]

    Changes in mGFR using Iohexol measurements in urine

18. Effective Renal Plasma Flow (ERPF) [After 13 weeks of treatment]

    Changes in ERPF using PAH-measurements in urine

19. Renal vascular resistance (RVR) [After 13 weeks of treatment]

    Changes in intrakidney hemodynamic function (Systemic Blood pressure / Renal Blood Flow)

20. Urine Albumine Creatinin Ratio [After 13 weeks of treatment]

    Changes in UACR concentration measured in urine.

21. Neutrophil gelatinase associated lipocalin (NGAL) [After 13 weeks of treatment]

    Changes in NGAL concentration measured in urine and serum

22. Kidney Injury marker 1 (KIM-1) [After 13 weeks of treatment]

    Changes in KIM-1 concentration measured in urine and serum

Other Outcome Measures

1. N-terminal pro Brain Natriuretic Peptide (NT-proBNP) [After 13 weeks of treatment]

   Changes in NT-proBNP measured in serum

2. Troponin T [After 13 weeks of treatment]

   Changes in Troponin T measured in serum

3. Clinical events [After 13 weeks of treatment]

   Comparison of the frequency of a combined safety endpoint of death, myocardial infarction and heart failure hospitalization

4. Serious Adverse Events (SAE's) [After 13 weeks of treatment.]

   Comparison of the frequency of Serious Adverse Events between both groups.

5. Treatment Emergent Adverse Events (TEAE's) [After 13 weeks of treatment.]

   Comparison of the frequency of Treatment Emergent Adverse Events between both groups.

6. Adverse events of specific interest (AESI's) [After 13 weeks of treatment]

   Comparison of the frequency of Adverse events of specific interest between both groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age≥ 50 years

2. Patients with a diagnosis of symptomatic chronic heart failure (New York Heart Association class II or III) AND preserved systolic LV function (LV ejection fraction or LVEF ≥ 50%) documented within the last 6 months AND evidence of diastolic LV dysfunction with at least 1 out of the following 4 criteria:

• HFA-PEFF score ≥5

• H2FPEF score ≥6

• HFpEF according to the 2021 ESC HF Guidelines (NT-proBNP>125 pg/ml AND either LV mass indexed or LVMI >95 g/m2 for women and >115 g/m2 for men OR left atrial volume indexed or LAVI >34 ml/m2 OR mean e; septal/lateral < 9 cm/s) OR E/e' >13 OR TR velocity at rest >2,8m/s.

• Pulmonary capillary wedge pressure (PCWP) >15 mmHg and/or >25 mmHg during exercise.

Exclusion Criteria:

1. Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs

2. Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months

3. Hemoglobin <9 g/dl at screening

4. LVEF <40% measured at any time point in the history of the patient

5. History of mitral valve repair or replacement

6. Presence of significant valvular disease defined as mitral valve regurgitation defined as grade ≥ 3+ MR; tricuspid valve regurgitation defined as grade ≥ 2+ TR; aortic valve disease defined as ≥ 2+ AR or > moderate AS

7. Acute myocarditis within 3 months prior to randomization

8. Infiltrative cardiomyopathy

9. Genetic cardiomyopathy

10. Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy

11. Precapillary pulmonary hypertension

12. BMI >40 kg/m2

13. Estimated glomerular filtration rate (GFR) <20 ml/min or >90 ml/min

14. History of solid organ transplantation including kidney transplantation

15. Atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm

16. Not able to undergo the complete study protocol

17. Doubt about compliance

18. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control

19. Chronic absorption problems

20. Proven allergy for lactose products or cow-milk.

21. Proven allergy for Iodide-containing contrast, Iohexol or PAH.

22. Any documented or suspected malignancy or history of malignancy within 1 year prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix

23. Currently enrolled in another investigational device or drug trial

24. Estimated life expectancy <1 year

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amsterdam UMC, location VUmc

Investigators

• Principal Investigator: Louis Handoko, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Principal Investigator: Adriaan Voors, MD, PhD, University Medical Center Groningen
• Principal Investigator: Loek van Heerebeek, MD, PhD, Onze Lieve Vrouwe Gasthuis, Amsterdam

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: M. Louis Handoko, MD, PhD, Cardiologist, Principal Investigator, Amsterdam UMC, location VUmc
• ClinicalTrials.gov Identifier: NCT05672134
• Other Study ID Numbers: NL 80684
• First Posted: Jan 5, 2023
• Last Update Posted: Jan 5, 2023
• Last Verified: Jan 1, 2023

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; Geranylgeranylacetone

Study Results

No Results Posted as of Jan 5, 2023